Bactericidal 4-chloro-2-cyclopentylphenol



United States Patent 3,323,988 BACTERICIDAL 4-CHLORO-2-CYCLO- PENTYLPHENOL Clarence L. Lorah, Midland, Mich., assignor to The Dow Chemical Company, Midland, Mich., a corporation of Delaware No Drawing. Filed Nov. 25, 1964, Ser. No. 414,007

4 Claims. (Cl. 167-31) from the disadvantages that it is a relatively weak antimicrobial, strongly irritant to living tissue of higher organsms, at concentrations which effectively depopulate areas of microorganisms; and it has a strong, unpleasant odor. When employed in the sanitation of, for example,

public places, in concentrations sufficient to destroy a 1 population of microorganisms, in a place in which incidental contact with living tissue is possible, such treated areas tend, by reason of phenol residue, to be malodorous and irritant to the living tissue.

In the attempt to find substances which are more active antimicrobials, but less odorous and, as used, distinctively less irritant, numerous substituted phenols have been made and tested. The properties of many of these substances have been carefully investigated. It has been 3,323,988 Patented June 6, 1967 whereas it is devoid of the limitations imposed by the phenomenon of quasi-specificity which is expected of compounds having alkyl substituents of the order of magnitude here represented.

The compound of the present invention is, as a composition of matter, known in the art. See German national Patent Number 615,448, published July 4, 1935, to Hoffmann-La Roche and Company, Example 8. However, as

. is commonplace in the patent practice of various foreign countries, this patent knows nothing, and teaches those skilled in the art nothing, of the control of any microorganisms.

Thus, in light of the art, what I have invented can more particularly be stated as the method of killing essentially all of a population of microorganisms that comprises the step of contacting that population with a microbiocidal amount of 4-chloro-2-cyclopentylphenol. Also, when the said population is a population of mixed microorganisms of which some are gram positive and others are gram negative, as is usually the case, the method remains fully effective, at essentially one and the same rate of application, minimal with respect to microbiocidal properties, and affords a complete kill of both kinds of microorganisms. This remains true, when one or more of the organisms represented in the population is a pathogen. Thus, it becomes apparent that in the present invention there is offered a phenol the use of which at very low concentrations affords control of mixed microorganism populations at rates of application of the phenol which leave, as residue upon a treated surface, an amount of the phenol so small as to be inoffensive; the substance ascertained that, in some instances, the halogenation of the aromatic nucleus of a phenol tends to increase both irritation and antimicrobial activity. In contrast, the alkylation of the aromatic nucleus of the phenol may, in many instances, reduce the antimicrobial activity and give rise also to a phenomenon which is known as quasispecificity. The term appears first to have been employed by Klarmann, see 55 Journal of the American Chemical Society, 2576 (1933), at 2578.

A quasi-specificantimicrobial substance is one which is specific in the sense that it tends effectively to control either those microorganisms responding to a gram stain as negative, or to those responding as positive, but not to control all of a mixed population of microorganisms of which some manifest one and some another gram stain reaction. Thus, as Klarman points out in the cited work, as the alkyl radical substituent upon a chlorophenol increases in number of carbon atoms, the quasi-specific phenomenon tends to become more and more distinctive. Also, 2-cycloalkyl-4-chlorophenols are expected to show the same quasi-specificity and only a fraction of the bactericidal potency of the corresponding straight-chain alkyl derivatives. See page 2579 of the cited article.

However, it has been desired to enjoy both the high antimicrobial activity of a phenol together with the reduction of tissue irritation of higher organisms that arises by reason of an alkyl substituent, without simultaneously bringing about to an unsatisfactory degree the quasispecific phenomenon, since this quasi-specificity represents a defined area of failure of the antimicrobial. To the time of the present invention, no such substance has been known.

I have discovered that the subject compound of the present invention, 4-chloro-2-cyclopentylphenol manifests a degree of antimicrobial (that is to say, microbiocidal) toxicity which is relatively very great as contrasted with its tendency to irritate living tissue of higher animals,

has the further distinctive advantage that it is essentially without the objectionable phenolic odor characterizing phenol itself, the cres-ols, and most antimicrobial substances related thereto.

Moreover, the process of the present invention results also in destruction of populations of acid-fast microorganisms including mixed populations of which some of the component members are acid-fast microorganisms.

Thus, in summary, the present process offers advantage over the prior art processes of killing microorganisms in that a complete kill of microorganisms of a broader biological spectrum is effected, employing rates of toxicant sufficiently low that irritant side effects and objectionable phenolic odors are almost completely eliminated.

Specific embodiments of the practice of this invention have been based upon the official methods for phenol coeflicient determination, methods 5.001 through 5.009, both inclusive, of Official Methods of Analysis of the Association of Oflicial Agricultural Chemists, 9th edition (Washington, 1960) pages 63-66, which is here incorporated by reference.

For convenience, all phenol compounds herein reported were brought into solution with the use of small amounts of isopropanol and of a commercial wetting agent described by its manufacturer as the sodium salt of a dodecylated, sulfonated diphenyl oxide; the adjuvants employed were employed in checks and were not antimicrobial to a statistically significant extent alone, as employed. All phenol solutions were clear, stable formulations. The odor of phenol was faint to imperceptible in the formulations of the 4-chloro-2-cyclopentylphenol, and distinct in the formulations of phenol.

In the antimicrobial tests, as a gram-negative organism, Salmonella typhosa was employed. As a gram-positive organism, Micrococcus pyogenes, var. aureus was employed.

The phenol coeficients thus derived, for not only 4- chloro-2-cyclopentylphenol, but for phenol, and also for numerous other substituted phenols tested for comparison, were then converted by a simple formula to a coefi'icient of quasi-specificity. In this conversion, the phenol both organisms, the coefficient of quasi-specificity is unity;

as activity against the gram-negative substances declines with increasing quasi-specificity, the coefiicient rises. It is pointed out that unity, or the numeral 1, represents theoretically perfect absence of quasi-specificity, and hence, highly desirable equal efiicacy in control of organisms of both gram-stain responses.

Following the designated procedures, the results obtained were as follows:

Phenol Coefficient Coeflicieut of Compound Tested Quasi- S. M. Specityphosa pyrogmcs ficity aurcus p-Cl1loro-o-n-pentylphenol l 66 650 11 p-Ohloro-o-cyclohexylpllenol 20 500 25 o-Chlro-pcyclopcntylphenol 2 200 100 o-Cyclopentyl-p-chlorophenol 222 232 1 When tested for efficacy against acid-fast bacteria, as represented by Mycobacterium smegmatis, the killing dilution of o-cyclopentyl-p-chl0rophenol was found to be l:l6,000: that is to say, for example, one gram 4-chloro- 2-cyc1opentylphenol per 16 kilograms resulting aqueous dispersion. This value indicates that it is highly effective against bacteria of this sort. The test microorganism has been widely used in investigation of efficacy of antimicrobial substances against acid-fast bacteria.

Also, 4-chloro-2-cyclopentylphenol is of relatively very low toxicity as compared with halogenated phenols, generally, or alkyl phenols, generally or as compared with other halogenated, alkylated phenols. This low toxicity is manifest as both a low tendency to skin irritation upon dermal contact, and a low acute oral toxicity in mammals, upon massive single dose ingestions, as compared to other phenols at rates and in concentrations to give approximately equivalent antimicrobial action.

The determination of a microbiocidal amount of the present microbiocide will not be difficult with reference to the data given, and the phenol coefficient test methods included by incorporation. However, the following values are representative.

When contacted, in aqueous dispersion in amounts of not less than about ten parts 4-chloro-2-cyclopentylphenol per million parts dispersion, all parts by weight with a population of microorganisms, the compound inhibits growth and multiplication of most or all of microorganisms contacted. Some microorganisms may be more or less resistant. Other factors, such as history of the population, ambient conditions, and the like, may need to be considered.

Similarly, at about 25 to 50 parts phenol compound per million parts aqueous dispersion, all parts by weight, the compound kills most or all microorganisms contacted.

When employed at about 200 parts phenol compound per million parts aqueous dispersion, all parts by weight, almost irrespective of population history or ambient conditions, microorganisms of almost all known species and strains are usually killed.

However, when it is believed that most or all the microorganisms are in a highly resistant spore form, it may be preferred to use the 4-chloro-2-cyclopentylphenol in aqueous dispersion in concentration of as much as two percent of weight of dispersion, at or near the temperature of boiling water C.), and for a period of 15 to 30 minutes.

The present microbiocide, 4-chloro-2-cyclopentylphenol, is active not only against bacteria, but also against microorganisms generally, comprising fungi and viruses, as well as other microorganisms including pathogenic microorganisms such as the Rickettsiae, the cercarial phase of trematodes, and the like.

I claim:

1. The method of killing essentially all of a population of bacteria comprising both gram-positive and gramnegative bacteria that comprises the step of contacting said population with a bactericidal amount of 4-chloro- 2-cyclopentylphenol.

2. Method of claim 1 wherein the population comprises a pathogen.

3. Method of claim 1 wherein the population comprises an acid fast microorganism.

4. Method of killing Micrococcus pyagenes aureus which comprises contacting said organism with 4-chloro- Z-cyclopentylphenol.

References Cited FOREIGN PATENTS 898,664 12/1953 Germany.

ALBERT T. MEYERS, Primary Examiner.

JEROME D. GOLDBERG, Assistant Examiner. 

1. THE METHOD OF KILLING ESSENTIALLY ALL OF A POPULATION OF BACTERIA COMPRISING BOTH GRAM-POSITIVE AND GRAMNEGATIVE BACTERIA THAT COMPRISES THE STEP OF CONTACTING SAID POPULATION WITH A BACTERICIDAL AMOUNT OF 4-CHLORO2-CYCLOPENTYLPHENOL. 